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Liposomes with improved drug retention for treatment of cancer

a technology of liposomes and cancer, applied in the field of liposome drug loading methods and compositions, can solve the problems that the liposome encapsulated metal ions in these applications are not employed for drug retention purposes, and achieve the effect of enhancing the retention of therapeutic agents

Inactive Publication Date: 2011-10-27
BRITISH COLUMBIA CANCER AGENCY BRANCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The invention also relates to a method of enhancing the retention of a therapeutic agent within liposomes comprising the steps of (a) providing within an interior of the liposomes an intra-liposomal solution comprising copper ions; (b) maintaining the pH of the intra-liposomal solution below 6.5; (c) providing a therapeutic agent in the external solution, wherein the therapeutic agent diffuses into the interior and is encapsulated within the liposomes, and wherein the presence of the copper ions enhances the retention of the therapeutic agent therein.

Problems solved by technology

The prior art does not teach methods and compositions that rely on divalent copper ions (Cu2+) in a low pH environment, and it was not anticipated that such compositions would result in improved drug retention attributes.
However, liposomally encapsulated metal ions in these applications are not employed for drug retention purposes.

Method used

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  • Liposomes with improved drug retention for treatment of cancer
  • Liposomes with improved drug retention for treatment of cancer
  • Liposomes with improved drug retention for treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1.0

1.1 Materials and Methods

1.1.1 Liposome Formation

[0046]DSPC / Chol (55:45 mol %) large unilamellar vesicles (LUVs) were prepared by the extrusion method. Briefly, lipids were dissolved in chloroform at the required molar ratio, labelled with the non-exchangeable, non-metabolizable lipid marker, 3H-CHE and dried to a thin film under a stream of nitrogen gas. Subsequently, the lipid was placed in a high vacuum for 3 hours to remove any residual solvent. The lipid films were then hydrated at 65° C. by mixing with the appropriate buffer (300 mM CuSO4, 300 mM CoSO4, 300 mM ZnSO4 and 300 mM MnSO4). The mixture was subjected to five cycles of freeze-and-thaw (5 minutes each, freezing in liquid nitrogen and thawing at 65° C.). The formed multilamellar vesicles (MLV's) were extruded 10 times through stacked polycarbonate filters of 0.1 μm pore size at 65° C. (Extruder, Northern lipids). The resultant LUVs typically possessed mean vesicular diameters in the range 110 nm±30 nm. The LUVs' externa...

example 2.0

2.1 Plasma Drug Retention

[0066]FIGS. 19 and 20 illustrate drug to lipid ratios in the plasma following in vivo administration to Rag-2M mice. In each case the administered formulations consisted of the same liposome composition with different internal solutions as indicated in the figure legends. In the case of both the drug irinotecan (FIG. 19) and vinorelbine (FIG. 20) the formulation prepared by Cu2+ / A23187 drug loading technology demonstrated significantly better plasma drug retention as indicated by the higher relative drug-to-lipid ratios.

2.2 Pharmacokinetic Parameters of Different Irinotecan Treatments

[0067]FIG. 21 is a table similar to FIG. 18 summarizing pharmacokinetic parameters of different irinotecan treatments. The delay in tumour growth was most effective in the case of the formulation prepared by Cu2+ / A23187 drug loading technology. In FIG. 21, irinotecan plasma-area-under-the-curve (AUC) was calculated using WinNonLin pharmacokinetic software (noncompartmental model...

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Abstract

The present invention relates to the use of copper ions to achieve enhanced retention of a therapeutic agent within a liposome. The invention may be employed to more effectively deliver a liposomally encapsulated therapeutic agent to a target site in vitro and in vivo for anti-cancer or other therapy. The liposome may comprise an interior buffer solution containing the therapeutic agent, the solution having a pH less than 6.5 and most preferably approximating pH 3.5. At least some of the copper ions are retained within the interior solution. In a particular embodiment the therapeutic agent may be a chemotherapeutic drug, such as irinotecan. The invention may also comprise an ionophore to facilitate loading of drug into the liposome. In one particular embodiment the combination of the ionophore A23187 and encapsulated divalent copper (Cu2+) resulted in an irinotecan formulation that exhibited surprisingly improved drug retention attributes.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional patent application Ser. No. 60 / 615,943 filed 6 Oct. 2004 which is hereby incorporated by reference.FIELD OF THE INVENTION[0002]This invention relates to a liposome drug loading method and composition that provides superior drug retention, enabling enhanced delivery of therapeutic compounds in vivo.BACKGROUND OF THE INVENTION[0003]Liposomes are microscopic particles that are made up of one or more lipid bilayers enclosing an internal compartment. Liposomes can be categorized into multilamellar vesicles, multivesicular liposomes, unilamellar vesicles and giant liposomes. Liposomes have been widely used as carriers for a variety of agents such as drugs, cosmetics, diagnostic reagents, and genetic material. Since liposomes consist of non-toxic lipids, they generally have low toxicity and therefore are useful in a variety of pharmaceutical applications. In particular, liposomes are useful for i...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/4375A61P35/00
CPCA61K9/127A61K47/02A61K31/4745A61P35/00
Inventor BALLY, MARCELRAMSAY, EUAN
Owner BRITISH COLUMBIA CANCER AGENCY BRANCH
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